Interim Effectiveness of Updated 2023–2024 (Monovalent XBB.1.5) COVID-19 Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalization Among Immunocompetent Adults Aged ≥18 Years — VISION and IVY Networks, September 2023–January 2024

In September 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccination for all persons aged ≥6 months to prevent COVID-19, including severe disease. However, few estimates of updated vaccine effectiveness (VE) against medically attended illness are available. This analysis evaluated VE of an updated COVID-19 vaccine dose against COVID-19-associated emergency department (ED) or urgent care (UC) encounters and hospitalization among immunocompetent adults aged ≥18 years during September 2023-January 2024 using a test-negative, case-control design with data from two CDC VE networks. VE against COVID-19-associated ED/UC encounters was 51% (95% CI = 47%-54%) during the first 7-59 days after an updated dose and 39% (95% CI = 33%-45%) during the 60-119 days after an updated dose. VE estimates against COVID-19-associated hospitalization from two CDC VE networks were 52% (95% CI = 47%-57%) and 43% (95% CI = 27%-56%), with a median interval from updated dose of 42 and 47 days, respectively. Updated COVID-19 vaccine provided increased protection against COVID-19-associated ED/UC encounters and hospitalization among immunocompetent adults. These results support CDC recommendations for updated 2023-2024 COVID-19 vaccination. All persons aged ≥6 months should receive updated 2023-2024 COVID-19 vaccine.


Introduction
On September 12, 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 COVID-19 vaccination with a monovalent XBB.1.5-derivedvaccine for all persons aged ≥6 months to prevent COVID-19, including severe disease (1).Although 1 updated vaccine dose is recommended for most persons aged ≥5 years, vaccination coverage with updated vaccines has remained low,* including among those at highest risk for severe disease, such as adults aged ≥65 years.Thousands of persons in the United States continue to be hospitalized with COVID-19 each week, including approximately 31,000 during January 7-13, 2024, despite endemicity and increased population immunity to SARS-CoV-2.† This analysis estimated updated COVID-19 vaccine effectiveness (VE) during September 2023-January 2024 § among immunocompetent adults aged ≥18 years against COVID-19-associated emergency department (ED) or urgent care (UC) encounters in one CDC VE network and VE against COVID-19-associated hospitalization in two CDC VE networks.

Data Collection
Methods for Virtual SARS-CoV-2, Influenza, and Other respiratory viruses Network (VISION) and Investigating Respiratory Viruses in the Acutely Ill (IVY) VE analyses have been described (2,3).VISION is a multisite, electronic health records (EHR)-based network including 369 EDs and UCs and 229 hospitals in eight states ¶ that uses a test-negative, of illness onset and 3 days of hospital admission.Nasal swabs are collected for central RT-PCR testing for SARS-CoV-2 at Vanderbilt University Medical Center (Nashville, Tennessee), and SARS-CoV-2-positive specimens are sent to the University of Michigan (Ann Arbor, Michigan) for whole genome sequencing to identify SARS-CoV-2 lineages.Demographic and clinical data are collected through EHR review and patient or proxy interview.COVID-19 vaccination history is ascertained from state or jurisdictional registries, EHRs, and self-report.

Data Analysis
The VISION and IVY networks conducted separate VE analyses.In both analyses, immunocompetent adults aged ≥18 years who 1) had a medical encounter at an ED/UC (VISION only) or 2) were hospitalized (VISION and IVY) at a participating facility with CLI were included.Case-patients were those who received a positive SARS-CoV-2 molecular test result, and control patients were those who received a negative SARS-CoV-2 test result.¶ ¶ Participants were excluded if they 1) received a COVID-19 vaccine dose <7 days before their eligible ED/UC encounter or hospitalization; 2) received an updated COVID-19 vaccine dose <2 months after receiving a previous COVID-19 vaccine dose (to align with current Advisory Committee on Immunization Practices recommendations); 3) received a bivalent COVID-19 vaccine dose after September 10, 2023;4) received an updated COVID-19 vaccine dose before September 13, 2023; or 5) received >1 updated COVID-19 vaccine dose.***Case-patients were also excluded if they had received a positive influenza or respiratory syncytial virus (RSV) molecular test result at the time of their CLI encounter.† † † Because of potential confounding caused by the association between COVID-19 and influenza vaccination behaviors, control patients who received positive or indeterminant influenza test results were excluded from the primary analysis § § § (4).A sensitivity analysis including these control patients was also conducted.
Odds ratios (ORs) and 95% CIs were estimated using multivariable logistic regression comparing persons who received an updated COVID-19 vaccine dose with those who did not, irrespective of the number of previous original or bivalent COVID-19 vaccine doses received (if any), among case-patients and control patients.VE models were adjusted ¶ ¶ In the IVY analysis, patients were also classified as case-patients if they received a positive SARS-CoV-2 antigen test result.*** In the IVY analysis, patients were also excluded if they experienced illness onset after hospital admission or withdrew.† † † One VISION site, representing 19% of case-patients from VISION analyses, did not provide RSV test results; therefore, RSV coinfections could not be excluded from this site.§ § § In the IVY analysis, patients with missing influenza test results were also excluded.
for age, sex, race and ethnicity, calendar time, and geographic region.¶ ¶ ¶ VE was calculated as (1 − adjusted OR) × 100%.In the VISION network, VE was estimated for adults aged ≥18 years and by age group (18-64 and ≥65 years).In the IVY network, statistical power was limited among younger adults because of lower vaccination coverage and fewer COVID-19associated hospitalizations among persons aged 18-64 years; therefore, VE against hospitalization was estimated only for adults aged ≥18 years and ≥65 years.
Analyses were conducted using R software (version 4.3.2;R Foundation) for the VISION analysis and SAS software (version 9.4; SAS Institute) for the IVY analysis.This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy.****This activity was reviewed and approved as a research activity by one VISION site.
Including control patients who received positive or indeterminant influenza test results added 1,819 control patients to the VISION hospitalization analysis and including control patients who received positive or indeterminant influenza test results or had missing influenza test results added 511 control patients to the IVY hospitalization analysis (Supplementary Table 1, https://stacks.cdc.gov/view/cdc/148434).VE estimates in supplementary analyses including control patients who received positive or indeterminant influenza test results did not differ meaningfully from those in the main analyses for ED/UC encounters (Supplementary Table 2, https://stacks.cdc.gov/view/cdc/148435) or hospitalization (Supplementary Table 3, https://stacks.cdc.gov/view/cdc/148436).
Whole genome sequencing data were available for SARS-CoV-2-positive specimens collected in the IVY network during September 21-December 15, 2023.Among 952 sequenced specimens, 154 (16%) had XBB.1.5-likespike proteins, 550 (58%) had EG.5-like spike proteins with an F456L substitution compared with XBB.1.5, 189 (20%)     * The "no updated dose" group included all eligible persons who did not receive an updated (2023-2024) COVID-19 vaccine dose, regardless of number of previous (i.e., original monovalent and bivalent) doses (if any) received.† For VISION, "Other, NH" race includes persons reporting NH ethnicity and any of the following for race: American Indian or Alaska Native, Asian, Native Hawaiian or other Pacific Islander, other races not listed, and multiple races; because of small numbers, these categories were combined.For IVY, "Other, NH" race includes Asian, Native American or Alaska Native, and Native Hawaiian or other Pacific Islander; because of small numbers, these categories were combined.§ For VISION, "Unknown" includes persons with missing race and ethnicity in their electronic health records.For IVY, "Unknown" includes patients who self-reported their race and ethnicity as "Other" and those for whom race and ethnicity were unknown.¶ Regions are defined by HHS.States included in each region are available at https://www.hhs.gov/about/agencies/iea/regional-offices/index.html.VISION network sites included were located as follows.* VE was calculated as (1 − odds ratio) × 100% with odds ratios calculated using multivariable logistic regression.For VISION, the odds ratio was adjusted for age, sex, race and ethnicity, geographic region, and calendar time (days since January 1, 2021).For IVY, the odds ratio was adjusted for age, sex, race and ethnicity, calendar time in biweekly intervals, and U.S. Department of Health and Human Services region.† The "no updated dose" group included all eligible persons who did not receive an updated (2023-2024) COVID-19 vaccine dose, regardless of number of previous (i.e., original monovalent and bivalent) doses (if any) received.§ Some estimates are imprecise, which might be due to a relatively small number of persons in each level of vaccination or case status.This imprecision indicates that the actual VE could be substantially different from the point estimate shown, and estimates should therefore be interpreted with caution.Additional data accrual could increase precision and allow more precise interpretation.
had HK.3-like spike proteins with L455F and F456L substitutions compared with XBB.1.5,57 (6%) had JN.1-like spike proteins with more than30 substitutions compared with XBB.1.5,and two (<1%) had other spike proteins.† † † † Similarly, among 18,316 SARS-CoV-2-positive specimens collected during the same period and sequenced by CDC as part of national genomic surveillance, § § § § 2,624 (14%) had XBB.1.5-likespike proteins, 9,649 (53%) had EG.5-like spike proteins, 3,700 (20%) had HK.Updated COVID-19 vaccines contain the spike antigen from the SARS-CoV-2 Omicron XBB.1.5virus, which was the predominant variant circulating in the United States during the first half of 2023.Many other XBB lineages cocirculated during fall 2023 that had amino acid substitutions associated with increased escape from neutralizing antibodies, such as EG. 5 and HK.3 (5).The JN.1 lineage, a descendent of Omicron BA.2.86, was first detected in the United States in September 2023 ¶ ¶ ¶ ¶ and accounted for approximately 65% of circulating lineages by the 2-week period ending January 6, 2024.*****As noted, JN.1 contains more than 30 substitutions in the spike protein compared with XBB.1.5,some of which might be associated with immune escape (5).Although studies have found that updated COVID-19 vaccines elicit broadly cross-protective neutralizing antibodies, including against XBB lineages and JN.1 (5)(6)(7), the pace and frequency with which new SARS-CoV-2 lineages have displaced predecessors underscores the need for ongoing monitoring of COVID-19 VE and for periodic COVID-19 vaccine antigen updates.These analyses include periods when XBB lineages and JN.1 cocirculated to varying degrees in the United States, indicating that receipt of updated vaccines provided protection against COVID-19-associated ED/UC encounters and hospitalization due to the variants cocirculating during this period.
Despite different populations, methods, and outcomes, estimates of the effectiveness of updated COVID-19 vaccines were aligned across the VISION and IVY analyses.VE ¶ ¶ ¶ ¶ h t t p s : / / w w w. c d c .g o v / r e s p i r a t o r y -v i r u s e s / w h a t s -n e w / SARS-CoV-2-variant-JN.1.html***** https://covid.cdc.gov/covid-data-tracker/#variant-proportionsestimates were also similar to those recently published from another CDC VE platform, which measured VE against symptomatic SARS-CoV-2 infection ( 8), and to a United Kingdom report, † † † † † which measured VE against hospitalization among patients aged ≥65 years.Earlier estimates of the effectiveness of updated COVID-19 vaccines against hospitalization in older adults from Denmark ( 9) and the Netherlands (10) were somewhat higher than those observed in this analysis; however, this is likely due to a shorter interval since updated dose receipt among patients included in the European studies or to differences in study methods.Whereas the maximum interval since receipt of an updated dose was 25 days in the Danish report and 2 months in the Dutch report, persons in the VISION and IVY analyses could have received an updated dose up to 4 months earlier.
In the VISION analysis, there was evidence of waning effectiveness of updated COVID-19 vaccines against ED/UC encounters; however, COVID-19-associated hospitalization rates during the analysis period were relatively low compared with previous years, limiting the evaluation of waning VE against hospitalization and precluding estimation of VE against critical illness.Analyses from VISION and IVY during 2022-2023 showed substantial waning of COVID-19 VE against ED/UC encounters and hospitalization, with VE not significantly different from zero in some strata by 6 months after vaccination, although VE was more sustained against critical illness (2,3) (defined as receipt of invasive mechanical ventilation, intensive care unit admission, or death), with protection lasting well over 1 year after the most recent dose.Continued monitoring of the effectiveness of updated COVID-19 vaccines for expected waning against hospitalization and to determine the durability of VE against critical illness is needed.

Limitations
The findings in this report are subject to at least five limitations.First, although case-patients were required to meet a CLI definition and to receive a positive SARS-CoV-2 test result, they might have visited EDs or UCs or been hospitalized for reasons other than COVID-19, which could have lowered VE estimates.Second, misclassification of vaccination status was possible, because state registries, EHRs, medical claims data, and self-report might not identify all updated COVID-19 vaccine doses administered, which would likely result in underestimation of VE.Third, analyses did not account for previous SARS-CoV-2 infection, which might provide protection against future COVID-19.VE should therefore be interpreted as the incremental benefit of an updated dose in a population † † † † † https://assets.publishing.service.

Abbreviations:
Abbreviations: ED = emergency department; HHS = U.S. Department of Health and Human Services; IVY = Investigating Respiratory Viruses in the Acutely Ill; NH = non-Hispanic; UC = urgent care; VE = vaccine effectiveness; VISION = Virtual SARS-CoV-2, Influenza, and Other respiratory viruses Network.*The "no updated dose" group included all eligible persons who did not receive an updated (2023-2024) COVID-19 vaccine dose, regardless of number of previous (i.e., original monovalent and bivalent) doses (if any) received.† For VISION, "Other, NH" race includes persons reporting NH ethnicity and any of the following for race: American Indian or Alaska Native, Asian, Native Hawaiian or other Pacific Islander, other races not listed, and multiple races; because of small numbers, these categories were combined.For IVY, "Other, NH" race includes Asian, Native American or Alaska Native, and Native Hawaiian or other Pacific Islander; because of small numbers, these categories were combined.§ For VISION, "Unknown" includes persons with missing race and ethnicity in their electronic health records.For IVY, "Unknown" includes patients who self-reported their race and ethnicity as "Other" and those for whom race and ethnicity were unknown.¶ Regions are defined by HHS.States included in each region are available at https://www.hhs.gov/about/agencies/iea/regional-offices/index.html.VISION network sites included were located as follows.Region 5: HealthPartners (Minnesota and Wisconsin) and Regenstrief Institute (Indiana); Region 8: Intermountain Healthcare (Utah) and University of Colorado (Colorado); Region 9: Kaiser Permanente Northern California (California); and Region 10: Kaiser Permanente Northwest (Oregon and Washington).IVY network sites were located as follows: Region 1: Baystate Medical Center (Springfield, Massachusetts), Beth Israel Deaconess Medical Center (Boston, Massachusetts), and Yale University (New Haven, Connecticut); Region 2: Montefiore Medical Center (New York, New York); Region 3: Johns Hopkins Hospital (Baltimore, Maryland); Region 4: Emory University Medical Center (Atlanta, Georgia), University of Miami Medical Center (Miami, Florida), Vanderbilt University Medical Center (Nashville, Tennessee), and Wake Forest University Baptist Medical Center (Winston-Salem, North Carolina); Region 5: Cleveland Clinic (Cleveland, Ohio), Hennepin County Medical Center (Minneapolis, Minnesota), Henry Ford Health (Detroit, Michigan), The Ohio State University Wexner Medical Center (Columbus, Ohio), and University of Michigan Hospital (Ann Arbor, Michigan); Region 6: Baylor Scott & White Medical Center (Temple, Texas) and Baylor University Medical Center (Dallas, Texas); Region 7: Barnes-Jewish Hospital (St. Louis, Missouri) and University of Iowa Hospitals (Iowa City, Iowa); Region 8: Intermountain Medical Center (Murray, Utah), UCHealth University of Colorado Hospital (Aurora, Colorado), and University of Utah (Salt Lake City, Utah); Region 9: Stanford University Medical Center (Stanford, California), Ronald Reagan UCLA Medical Center (Los Angeles, California), and University of Arizona Medical Center (Tucson, Arizona); and Region 10: Oregon Health & Science University Hospital (Portland, Oregon) and University of Washington (Seattle, Washington).** VISION underlying condition categories included pulmonary, cardiovascular, cerebrovascular, musculoskeletal, neurologic, hematologic, endocrine, renal, and gastrointestinal.IVY underlying condition categories included pulmonary, cardiovascular, neurologic, hematologic, endocrine, renal, gastrointestinal, and autoimmune.† † The JN.1 predominant period was considered to have started December 24, 2023.
gov.uk/media/65b3c8a3c5aacc000da683d3/ vaccine-surveillance-report-2024-week-4.pdfUS Department of Health and Human Services | Centers for Disease Control and Prevention | MMWR | February 29, 2024 | Vol.73 | No. 8with high levels of infection-induced immunity, vaccineinduced immunity, or both.Fourth, although analyses were adjusted for relevant confounders, residual confounding from other factors, including behavioral modifications to prevent SARS-CoV-2 exposure and outpatient antiviral treatment for COVID-19, is possible.Finally, sample size limitations precluded estimation of lineage-specific VE and stratification of VE by interval since updated dose receipt in the IVY analysis.Implications for Public Health PracticeIn this analysis of the effectiveness of updated COVID-19 vaccines, receipt of an updated COVID-19 vaccine dose provided protection against COVID-19-associated ED/UC encounters and hospitalization among immunocompetent adults.CDC will continue monitoring VE of updated COVID-19 vaccines.These results support CDC recommendations for updated 2023-2024 COVID-19 vaccination.All persons aged ≥6 months should receive updated 2023-2024 COVID-19 vaccine.

of COVID-19-associated ED/UC encounter
See table footnotes on the next page.
Abbreviations: Ref = referent group; VE = vaccine effectiveness; VISION = Virtual SARS-CoV-2, Influenza, and Other respiratory viruses Network.* VE was calculated as (1 − odds ratio) × 100% with odds ratios calculated using multivariable logistic regression.For VISION, the odds ratio was adjusted for age, sex, race and ethnicity, geographic region, and calendar time (days since January 1, 2021).†